Amyloid p-peptide (A[3) accumulation and toxicity in the brain are central events in the pathogenesis of Alzheimer's disease (AD). The low-density lipoprotein receptor-related protein (LRP) interacts with p- amyloid-precursor protein (APR) and regulates its endocytic trafficking and processing to Ap. LRP is also the major endocytic receptor for apolipoprotein E (apoE), which interacts with Ap and modulates its cellular clearance. Previous studies have detected abundant functional soluble LRP (sLRP) in peripheral and our preliminary work has detected sLRP in human brain and cerebral spinal fluid (CSF). Molecular and cellular studies have defined Notch/APP-like sequential processing of LRP by matrix metalloprotease (MMP) and by P- and y-secretases. Our long-term goal is to understand how LRP proteolysis is regulated in the brain and dysregulated during AD, and how these proteolytic events and processing products impact its function in APP trafficking and processing to Ap. Our preliminary studies have shown that a y-secretase cleavage product, APP intracellular domain (AICD), regulates LRP expression and function by directly binding to LRP promoter. Our studies also identified a novel adaptor protein, sorting nexin 17 (SNX17), that modulates endocytic trafficking and processing of both LRP and APP. Our central hypothesis is that LRP proteolytic processing is dysregulated in AD by altered expression and function of its processing enzymes and intracellular adaptor proteins and this in turn impairs LRP function in apoE metabolism and signaling in the brain. We propose four specific aims to test our hypothesis: 1) to identify LRP shedding enzymes and examine the functional impacts of altered LRP shedding on apoE metabolism and signaling; 2) to study how APP and other y-secretase substrates regulate LRP expression, processing and function; 3) to analyze how altered endocytic trafficking of LRP and APP by neuronal adaptor proteins influences their proteolytic processing, apoE metabolism and Ap production; and 4) to examine how LRP proteolysis and the expression of its processing enzymes and adaptor proteins are altered in unique AD transgenic mouse models and during aging and AD in human. Through collaborations with the other projects, our goal in this program project is to define the mechanism of apoE receptor processing and effects on their functions. Our proposed studies may identify novel targets for AD diagnosis and therapy.